Liver growth and differentiation are processes critical to metabolic adaptation of the newborn. Perturbation of these processes contributes to neonatal disorders and to the fetal origins of adult metabolic disease. The biology of fetal liver development also has implications for cell-based therapy for liver disease, hepatic carcinogenesis and the regulation of fetal somatic growth. This application is for continuation of a project that has focused on late gestation liver development in the rodent. The project has been based on the central hypothesis that fetal liver development in late gestation is regulated by mechanisms distinct from those that control liver function and mass in the adult. During the past cycle, our work focused on signaling by the mechanistic Target of Rapamycin (mTOR), a nutrient-sensing Ser/Thr kinase. We found that fetal rat hepatocytes are resistant to the anti-proliferative actions of the mTOR inhibitor, rapamycin. This observation led us to refocus our efforts on the identification of novel mechanisms for nutrient-responsive gene regulation, metabolic control and cell signaling in the fetus. We plan to identify such mechanisms by focusing on two comparisons, the late gestation fetal rat versus postnatal animals, 1 day to 35 days of age, and the normal late gestation fetus versus the intrauterine growth restricted fetus. We will study immunopurified fetal and postnatal hepatocytes using standard biochemical and cell biology methods and -omic approaches to achieve a long term goal of better understanding the nutrient regulation of fetal somatic growth. We propose the following specific aims. In Specific Aim 1, we will identify nutrient-responsive mechanisms that regulate fetal and perinatal hepatic gene expression. We will test the hypothesis that late gestation fetal-to-postnatal differences in hepatic gene expression involve the modification of histones and resulting changes in chromatin structure, and that this mode of transcriptional control mediates effects of nutrient restriction induced by maternal fasting late in gestation (E18 to E20). In Specific Aim 2, we will characterize the mechanisms that regulate nutrient- responsive mRNA translation in late gestation and newborn hepatocytes. Based on our studies showing differences in regulation of protein synthesis in fetal versus adult liver, we will focus on the hypothesis that differential expression of protoeforms of the eukaryotic translation initiation factor eIF4G1 is critical to nutrient- mediated fetal translation control. In Specific Aim 3, we will study the regulation of mitochondrial biogenesis and metabolism during the perinatal transition and in normal and growth restricted fetal rats. We will test the hypothesis that nutrient restriction late in gestation induces fetal hepatic mitochondrial biogenesis, a reduction in fermentative glycolysis and an increase in oxidative phosphorylation. Our preliminary studies and published data link mitochondrial biogenesis to translation control and mitochondrial metabolism to epigenetic regulation of gene expression. We anticipate that the completion and integration of our three specific aims will advance our understanding of nutrient-mediated regulation of fetal growth and metabolism during late gestation.